Resistance to polyoma virus-induced tumors correlates with CTL recognition of an immunodominant H-2Dk-restricted epitope in the middle T protein.
The natural mouse pathogen polyoma virus is highly oncogenic in H-2k mice carrying the endogenous superantigen encoded by the mouse mammary tumor provirus Mtv-7. This superantigen results in deletion of Vbeta6 TCR-expressing polyoma-specific CD8+ CTL, which appear to be critical effectors against polyoma tumorigenesis. Here we have isolated cloned lines of CD8+ T cells from resistant (i.e., Mtv-7-) H-2k mice that specifically lyse syngeneic polyoma virus-infected cells and polyoma tumor cells. Nearly all these CTL clones express Vbeta6 and are restricted in their recognition of virus-infected cells by H-2Dk. Screening a panel of synthetic peptides predicted to bind to Dk, for which no consensus peptide binding motif is known, we identified a peptide corresponding to a nine-amino acid sequence in the carboxyl-terminus of the middle T (MT) protein (amino acids 389-397) that was recognized by all the Vbeta6+ CD8+ CTL clones. The inability of MT(389-397)-reactive CTL to recognize cells infected with a mutant polyoma virus encoding a MT truncated just proximal to this sequence indicates that MT(389-397) is a naturally processed peptide. The frequencies of precursor CTL specific for polyoma virus and MT(389-397) peptide were similar, indicating that MT(389-397) is the immunodominant epitope in H-2k mice. In addition, polyoma-infected resistant mice possess a 10- to 20-fold higher MT(389-397)-specific precursor CTL frequency than susceptible mice. This highly focused CTL response to polyoma virus provides a valuable animal model to investigate the in vivo activity of CTL against virus-induced neoplasia.
Lukacher
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AE
Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA. alukach@emory.edu
Wilson
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CS
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology*; D002460:Cell Line; D002469:Cell Separation; D002999:Clone Cells; D004198:Disease Susceptibility; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006183:H-2 Antigens / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate; D016056:Immunodominant Epitopes / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D030361:Papillomavirus Infections / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011120:Polyomavirus / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014412:Tumor Virus Infections / Q000276:immunology*
D000952:Antigens, Polyomavirus Transforming; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D016056:Immunodominant Epitopes; D010446:Peptide Fragments